The present invention relates to the derivatives of specially substituted azole compounds which have improved antifungal activity as compared to known compounds such as fluconazole and itraconazole and the processes for the preparation thereof. This invention also relates to pharmaceutical compositions containing the compounds of the present invention and their use in treating and/or preventing fungal infections in mammals, preferably humans.
Life-threatening, systemic fungal infections continue to be a significant problem in health care today. In particular, patients who become xe2x80x9cimmuno-compromised: as a result of diabetes, cancer, prolonged steroid therapy, organ transplantation antirejection therapy, the acquired immune deficiency syndrome (AIDS) or other physiologically or immunologically compromising syndromes, are especially susceptible to opportunistic fungal infections. Most of these infections are caused by opportunistic pathogens, like species of Candida and Aspergillus and Cryptococcus neoformans. During the last 20 years, the incidence of sepsis fungal infection caused by candida species has increased significantly in debilitated and immuno-compromised patients. In addition, the more aggressive and frequently used broad spectrum antibiotic, antineoplastic and immunosuppressive chemotherapies have also augmented fungal infections.
Cryptococcosis is a leading cause of morbidity among AIDS patients. The incidence of life threatening cryptococcal infection among these patients have been estimated to vary from 10 to 30%. During initial therapy, 10 to 20% of these patients die and 30 to 60% patients succumb within a year. Amphoteracin B has changed disseminated cryptococcosis from uniformly fatal infection to curable infection but since Amphoteracin B penetrates the central nervous system poorly, interventricular AID injection may have to be administered for successful management of severe cases of patients with cryptococcal meningitis. Invasive aspergillosis has also become a leading cause of death, mainly among patients suffering from acute leukaemia or after allogenic bone marrow transfusion and after cytotoxic treatment of these conditions. It also occurs in patients with condition such as AIDS and chronic granulomatous disease. At present, only Amphoteracin B and itraconazole are available for treatment of aspergillosis. Inspite of their activity in-vitro, the effect of these drugs in-vivo against Aspergillus fumigatus remains low and as a consequence mortality from invasive aspergillosis remains high.
In addition, the emergence of fluconazole-resistant isolates of pathogenic yeasts, particularly in HIV-positive patients, and the general nature of treating fungal infections caused by Aspergillus species, are of growing concerns among infections disease specialists. The precise incidence of infections caused by Aspergillus species is difficult to determine due to lack of accurate, reliable diagnostic methodologies and poor diagnosis. The majority of Aspergillus infections in AIDS patients occur in late stage disease when immune cell functions are minimal. Impaired neutrophil and macrophage function is related to increased infection rates with Aspergillus species. The most common species of Aspergillus causing disease in AIDS patients are A. fumigatus (83%), A. flavus (9%), A. niger (5%) and A. terreus (3%).
Within the available drugs to treat fungal infections, the azole class appears to be most promising. This class of compounds inhibits the biosynthesis of ergosterol in fungi, which is the main constituent of fungal cell membrane. Of the various representative antifungals, early azoles used were miconazole, clotrimazole and tioconazole, which were potent against a wide range of fungi pathogenic to human. However, their in-vitro activity was not well exhibited in in-vivo models due to poor oral bioavailability and metabolic vulnerability. Ketoconazole was the first drug that could be used against systemic fungal infection and successfully delivered through oral route. However, it was still quite susceptible to metabolic inactivation and also caused impotence and gynacomastia probably due to its activity against human cytochrome P450 enzymes.
Fluconazole is the current drug of choice for treatment of severe infections caused by Candida species and C. neoformans. However, fluconazole has only weak activity against isolates of Aspergillus species [minimum inhibitory concentration (MIC) values of 400 xcexcg/ml], since the drug has low potency (IC50=4.8 xcexcM) against lanosterol 14xcex1xe2x80x94demethylase, the target enzyme in the fungus. Itraconazole, another triazole antifungal compound, generally is more active than fluconazole in the treatment of aspergillosis, but its activity in the clinic remains mixed as it showed variable oral availability, low solubility and caused ovarian cancer in animals. This may be due to its high protein binding properties.
Thus, the antifungals available in the market suffer with drawbacks such as, toxicity, narrow spectrum of activity and fungistatic profile rather fungicidal. Some of them also exhibit drug-drug interactions and, as a result, therapy becomes very complex. In view of the high incidence of fungal infections in immunocompromised patients and the recent trends for the steady increase of the populations of such patients, demands for new antifungal agents with broad spectrum of activity and good pharmacokinetic properties has increased. Thus, the continuing demand for safe and effective broad spectrum antifungal agent with favourable pharmacokinetic properties has spurred both the design and development of new systemically active antifungal triazoles. The development of earlier compounds which were referred to as second generation triazoles and which included SCH 39304 (Genaconazole), SCH42427 (Saperaconazole) and BAY R 8783 (Electrazole) had to be discontinued as a result of safety concerns. Another promising second generation triazole, D0870, a derivative of fluconazole, exhibited significant variations in plasma pharmacokinetics besides having weak antiaspergillus activity. Other fluconazole derivatives in different stages of development include voriconazole and ER 30346 (BMS 207147). Voriconazole also shows non-linear pharmacokinetics besides some concern regarding its ocular toxicity, while ER 30346""s anti-aspergillus activity, both in vitro and in vivo, is at best, only equal to itraconazole""s activity. SCH 56592, is a hydroxylated analogue of itraconazole with potent in-vitro and in-vivo activity, but is undetectable even when the serum drug concentration after several days of treatment are 25 to 100 times above the MIC for the most resistant C. neoformans. Thus, the potent activity of SCH 56592 for C.neoformans is partially negated by its low concentration at the site of infection to the central nervous system. The above azole candidates are discussed in the following publications: SCH 56592; Antimicrob. Agents Chemother, 40, 1910 (1996); 36th Interscience conference Antimicrob Agents Chemother, September, 1996, New Orleans, Abst. F87-F102; TAK-187; 36th Interscience conference Antimicrob Aqents Chemother, September, 1996, New Orleans, Abst. F74; EP 567892; ER-30346: Drugs of the Future, 21, 20 (1996).
Various compounds having thiol, sulphone, sulphonamides, N-di-substituted sulphonamides, triazoles and tetrazoles of the second asymmetric centre of fluconazole with various side chains have been covered in U.S. Pat. Nos. 5,466,820; 5,371,181 and 5,371,101 assigned to Takeda. But none of them satisfies the above-described medical needs completely, either being weak in spectrum, potency, safety or having undesired pharmacokinetics.
Despite the therapeutic success of fluconazole and itraconazole, there remains a significant need for improved, broad spectrum, better tolerated, less toxic, more potent antifungal compounds with minimal potential for development of resistance among target fungi.
The present invention relates to new substituted azole compounds which can be utilized to treat and/or prevent the fungal infections in mammals, preferably in humans.
The first aspect of the present invention provides compounds of Formula IA and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, 
wherein X is selected from the group consisting of CH2, CO, CS, SO2 and xe2x80x94Nxe2x95x90Nxe2x80x94;
R is selected from the group consisting of (1) C1-C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino (2) C1-C4 alkoxy, (3) halogen (4) formyl, (5) carboxyl (6) C1-C4 acyloxy, (7) phenyl or substituted phenyl, (8) hydroxy, (9) nitro (10) amino (11) furyl, (12) triazolyl, (13) thienyl, (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl;
R1 and R2 are each independently (1) hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino; (3) nitro, (4) amino (5) cyano, (6) carboxyl or protected carboxyl (7) SO2Rxe2x80x2 wherein Rxe2x80x2 is alkyl or aryl and (8) C1-C4 alkoxy;
Y is a phenyl group which is unsubstituted or substituted by substituents each independently selected from the group consisting of (1) halogen (2) nitro, (3) amino, (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4 alkoxy and (8) SO2Rxe2x80x2 wherein Rxe2x80x2 is hydrogen alkyl or aryl;
R3 is selected from the group consisting of hydrogen, C1-C4 alkyd group, halogen, hydroxy, C1-C4 alkoxy, nitro, amino, cyano, carboxyl and SO2Rxe2x80x2 wherein Rxe2x80x2 is hydrogen, alkyl or aryl; and
X1, X2, Y1, Y2 and Z are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C1-C4 alkyl, C1-C4 alkoxy, carboxyl or protected carboxyl.
When R1 is other than hydrogen, Formula IA has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR.
According to the second aspect of the present invention, there are provided compounds of Formula IB, and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, 
wherein X, R, R1, R2, Y and R3 are the same as defined earlier,
R4 is selected from the group consisting of hydrogen, C1-C4 alkyl group which is unsubstituted or substituted, B is selected from oxygen and sulphur atoms; and
R5 is selected from the group, (1) hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1-C4 alkyl which is unsubstituted or substituted with 1-3 substituted each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 alkoxy (g) C1-C4 alkoxycarboxyl amino (h) phenyl or naphthyl oxycarbonyl amino (i) semicarbazido (j) formamido (k) thioformamide (l) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF3 and (u) OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1-C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino (b) halogen, (c) (C1-C4 alkyl) halo (d) C1-C4 alkoxy (e) hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (l) tetrafluoropropyl and (m) tetrafluoropropoxyl.
When R1 is other than hydrogen, Formula IA has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR.
According to the third aspect of the present invention there are provided compounds of Formula II and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, 
wherein X, R, R1, R4, R5, B and Y have the same meanings as defined earlier.
When R1 is other than hydrogen, Formula II has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR.
The fourth aspect of the present invention provides compounds of Formula III and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, 
wherein X, R, R1, Y, B and R5 have the same meanings as defined above.
When R1 is other than hydrogen, Formula III has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention relates to the mixture of enantiomers as well as individual isomers and the most preferred in this situation is RR.
Pharmaceutically acceptable, non-toxic, acid addition salts of the compounds of the present invention of Formulae IA, 1B, II and III may be formed with inorganic or organic acids, by methods well known in the art.
It is further object of the invention to provide compositions containing the novel compounds of the present invention in the treatment of fungal infections.
The present invention also includes within its scope prodrugs of the compounds of Formulae IA, IB, II and III. In general, such prodrugs will be functional derivatives of these compounds which readily get converted in vivo into defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known.
The invention also includes pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, prodrugs, metabolites of the above formulae in combination with pharmaceutically acceptable carriers and optional excipients.
Other advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by the practice of the invention.
In order to achieve the above mentioned aspects and in accordance with the purpose of the invention as embodied and described herein, there are provided processes for the syntheses of compounds of Formulae IA, 1B, II and III, wherein R, R1, R2, R3, R4, R5, X, Y, X1, Y1, X2, Y2, Z and B are the same as defined earlier. The compounds of Formulae IA, 1B, II and III of the present invention may be prepared by following the reaction sequences as depicted below in schemes IA, IB to IX. 
In Scheme IA there is provided a process for preparing a compound of Formula IA, as shown above, wherein
X is selected from the group consisting CH2, CO, CS, SO2 and xe2x80x94Nxe2x95x90Nxe2x80x94,
R is selected from the group consisting of (1) C1-C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino (2) C1-C4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C1-C4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl,
R1 and R2 are each independently selected from the group consisting of (1) hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino (3) nitro (4) amino (5) cyano (6) carboxyl or protected carboxyl (7) SO2Rxe2x80x2 wherein Rxe2x80x2 is hydrogen, alkyl or aryl and (8) C1-C4 alkoxy, Y is a phenyl group which is unsubstituted or substituted by substituents each independently selected from the group consisting of (1) halogen (2) nitro (3) amino (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy (7) C1-C4 alkoxy and (8) SO2Rxe2x80x2 wherein Rxe2x80x2 is hydrogen, alkyl or aryl,
R3 is selected from the group consisting of hydrogen. C1-C4 alkyl group, halogen, hydroxy, C1-C4 alkoxy, nitro, amino, cyano, carboxyl and SO2Rxe2x80x2 wherein Rxe2x80x2 is hydrogen, alkyl or aryl; and
X1, X2, Y1, Y2 and Z are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C1-C4 alkyl, C1-C4 alkoxy, carboxyl or protected carboxyl.
Also, when R1 is other than hydrogen, Formula I has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS, this invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR, which comprises reacting 1-[2-(2,4-disubstituted phenyl)-2,3-epoxy derivative of 1,2,4-triazole of Formula IV, wherein X, R and R1, are the same as defined above, with triazol-3-one derivatives of Formula V, wherein R2, R3, X1, X2, Y, Y1, Y2 and Z have the same meanings, as defined above, in the presence of sodium hydride to afford the desired compound of Formula IA, wherein X, X1, X2, Y1, Y2, Z, R, R1, R2 and R3 have the same meanings as defined above. 
In Scheme IB there is provided a process for preparing a compound of Formula IB, wherein X, R, R1, R2, R3 and Y are the same as defined above, R4 is selected from the group hydrogen, C1-C4 alkyl group which is unsubstituted or substituted, B is selected from oxygen and sulphur atoms, R5 is selected from the group (1) hydrogen, (2) C1-C4 alkyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C1-C4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino (b) C1-C4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C1-C4 acyloxy (g) C1-C4 alkoxycarbonyl amino (h) phenyl or naphthyl-oxy carbonylamino (i) semicarbazido (j) formamido (k) thioformamido (l) hydroxy (m) nitro (n) amino (o) furyl (p) triazolyl (q) thienyl (r) oxazolyl (s) imidazolyl (t) CF2 and (u) OCF3 (4) naphthyl or naphthyl (C1-C4 alkyl) which may be substituted with 1-6 substituents selected from (a) C1-C5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy and amino, (b) halogen (c) (C1-C4 alkyl) halo, (d) C1-C4 alkoxy (e) hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (l) tetrafluoropropyl and (m) tetrafluoropropoxyl.
Also, when R1 is other than hydrogen, Formula I has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS, this invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR, which comprises reacting a compound of Formula ID wherein X, R, R1, R2, R3 and Y have the same meanings as defined earlier, with a compound of Formula R5xe2x80x94Nxe2x95x90Cxe2x95x90B wherein R5 and B are the same as defined earlier to give a compound of Formula IC, which on reaction with R4Z wherein R4 is the same as defined above and Z is any halogen atom, gives a compound of Formula IB wherein X, R, R1, R2, R3, R4, R5, Y and B have the same meanings as defined earlier. 
In Scheme II, there is provided a process for preparing a compound of Formula IA, wherein X, R, R1, R2, R3, Y, X1, X2, Y1, Y2 and Z are the same as defined above, also when R1 is other than hydrogen, Formula I has two asymmertric centres and there are four possible enantiomers i.e. RR, RS, SR and SS, this invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR, which comprises reacting epoxide derivative of Formula VI, wherein X, R, R1, R2, R3, X1, X2, Y, Y1, Y2 and Z are the same as defined above with 1,2,4-triazole to afford a compound of Formula IA. 
There is provided a process for preparing a compound of Formula II, wherein X, R, R1, R4, R5, Y and B have the same meanings as defined earlier, also when R1 is other than hydrogen, Formula II has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS, this invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR, which comprises reacting a compound of Formula VII, wherein R, R1, X and Y are same as defined earlier with a compound R5xe2x80x94Nxe2x95x90Bxe2x95x90B, wherein R5 and B are the same defined earlier to give a compound of Formula VIII, wherein R, R1, R5, X, Y and B have the same meanings as defined earlier. The compound of Formula VIII, on reaction with R4Z, wherein R4 is C1-C4 alkyl and Z is any halogen atom, gives a compound of Formula II, wherein R, R1, R4, R5, X, Y and B are the same as defined earlier. 
In scheme IV there is provided a process for the preparation of a compound of Formula III, wherein R, R1, R5, X, Y and B are the same as defined above, also when R1 is other than hydrogen, Formula III has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS, this invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR, which comprises reacting a compound of Formula IX with a compound of Formula Bxe2x95x90Cxe2x95x90Nxe2x80x94R5 wherein B and R5 are the same as defined earlier, to give the desired compound of Formula III. 
In Scheme V 1,3-difluorobenzene of Formula X, on treatment with chloroacetyl chloride of Formula XI, in the presence of a Lewis acid catalyst such as aluminium trichloride gives xcex1-chloro-2,4-difluoroacetophenone of Formula XII. This compound of Formula XII is further reacted with 1,2,4-triazole to obtain 2-(1H-1,2,4-triazol-1-yl)-2xe2x80x2-4xe2x80x2-difluoroacetophenone of Formula XIII. This compound of Formula XIII is further reacted with trimethyl sulphoxonium iodide (TMSI) to afford 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole of Formula IV (R=F, X=CH2, R1=H). The procedure as described in U.S. Pat. No. 4,404,216 is followed to prepare compound of Formula IV.
The triazol-3-one derivatives of Formula V (R3=H, Y=C6H4xe2x80x94), wherein R2, X1, X2, Y1, Y2 and Z are the same as defined earlier, are prepared by reacting substituted phenyl piperazine of Formula XIV, wherein X1, X2, Y1, Y2 and Z are the same as defined earlier, is reacted with 4-chloronitrobenzene to give the corresponding nitroaryl compound of Formula XV, which on catalytic reduction affords the anilino derivative of Formula XVI. The compound of Formula XVI, is acylated with phenyl chloroformate to afford phenyl carbamate derivatives of Formula XVII. Reaction of these carbamate derivative of Formula XVII, with hydrazine hydrate yields semicarbazide derivative of Formula XVIII, which on cyclization with formamidine derivatives gives the triazol-3-one derivatives of Formula V(R3=H, Y=C6H4xe2x80x94). The reaction of compound of Formula V, with the compound of Formula IV (R=F, R1=H, X=CH2) is carried out in the presence of sodium hydride to afford the desired compound of Formula IA (X=CH2, R=F, R1=H, Y=C6H4xe2x80x94, R3=H), wherein R2, X1, X2, Y1, Y2 and Z are the same as defined earlier. 
The compounds of Formula IA (X=CH2, R=F, R1=CH3, Y=C6H4xe2x80x94, R3=H) wherein R2, X1, Y1, X2, Y2 and Z have the same meanings as defined earlier, are synthesized following the reaction sequence embodied in Scheme VI. Thus, 1,3-difluorobenzene of Formula X is reacted with racemic (xc2x1)2-chloropropionyl chloride of Formula XIX to give a compound (xc2x1)2-chloro-2-methyl-2xe2x80x2,4xe2x80x2-difluoroaceto-phenone of Formula XX. The intermediate of Formula V which in turn is prepared by following the reaction sequence as described in Scheme V wherein R2, X1, X2, Y1, Y2 and Z have the same usual meanings, is condensed with (xc2x1)2-chloro-2-methyl-2xe2x80x2,4xe2x80x2-difluoroacetophenone of Formula XX in the presence of sodium hydride to afford compound of Formula XXI, wherein R2, X1, X2, Y1, Y2 and Z have the same meanings as defined earlier. The compound of Formula XXI is epoxidized with trimethyl-sulphoxonium iodide (TMSI) in dimethylsulfoxide (DMSO) to give an epoxide derivative of Formula VI (X=CH2, R=F, R1=CH3, Y=C6H4xe2x80x94, R3=H), which is then condensed with 1,2,4-triazole to give a compound of Formula IA (X=CH2, R=F, R1=CH3, Y=C6H4xe2x80x94, R3=H), wherein R2, X1, Y1, X2, Y2 and Z are the same as defined earlier. 
The compounds of Formula II (X=CH2, R=F, R1=H, Y=C6H4xe2x80x94 wherein R4, R5, and B have the same meanings as defined earlier, are synthesized by following the reaction sequence as depicted above in Scheme VII. Thus, 2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazolyl)-1-[4-(piprazinyl)phenoxy]-propan-2-ol of Formula VII (X=CH2, R=F, R1=H, Y=C6H4xe2x80x94) (prepared by the process as disclosed in U.S. Pat. No. 5,023,258, assigned to Pfizer) on treatment with the compound of Formula B=C=Nxe2x80x94R5, wherein B and R5 are the same as defined earlier gives a compound of Formula VII (X=CH2, R=F, R1=H, Y=C6H4xe2x80x94) wherein R5 and B are the same as defined earlier. This compound of Formula VII (X=CH2, R=F, R1=H, Y=C6H4xe2x80x94) is further reacted with R4Z in the presence of sodium hydride gives the required compound of Formula II (X=CH2, R=F, R1=H, Y=C6H4xe2x80x94, wherein R4, R5 and B are the same as defined earlier. 
In Scheme VII, 2-chloro-methyl-2xe2x80x2,4xe2x80x2-difluoroacetophenone of Formula XXII, on treatment with 1-acetyl-4-hydroxyphenylpiperazine of Formula XXIII, gives 2-[4-(4-acetylpiperazine)phenoxy]-2-methyl-2xe2x80x2,4xe2x80x2-difluoroacetophenone of Formula XXIV in the presence of potassium carbonate in dimethylformamide, which on treatment with trimethyl sulphoxonium iodide (TMSI) in DMSO gives the corresponding epoxide of Formula XXV. This compound of Formula XXV is reacted with 1,2,4-triazole to yield a compound of Formula XXVI, which in turn on hydrolysis with sodium hydroxide in dioxane gives a compound of Formula VII (X=CH2, R=F, R1=CH3, Y=C6H4xe2x80x94). The compound of Formula VII on reaction with R5xe2x80x94N=B=B gives a compound of Formula II (X=CH2, R=F, R1=CH3, R4=H) wherein R5 and B have the same meanings as defined earlier. 
In Scheme IX 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole of Formula IV (R=F, X=CH2, R1=H) on treatment with N-methyl-4-nitroaniline of Formula XXVII gives 3-[N-Methyl-N-(4-nitrophenyl)]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazolyl)-propan-3-amino-2-ol of Formula XXVIII which on reduction with palladium on charcoal gives 3-[N-Methyl-N-(4-aminophenyl)]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazolyl)-propane-3-amino-2-ol of Formula IX, (X=CH2, R=F, R1=H, Y=C6H4xe2x80x94) which on reaction with B=C=Nxe2x80x94R5 gives a compound of Formula III (X=CH2, R=F, R1=H, Y=C6H4xe2x80x94) wherein B and R5 are the same as defined earlier.
In the above schemes where specific acids, bases, solvents, catalysts, oxidising agents, reducing agents etc. are mentioned, it is to be understood that the other acids, bases, solvents, catalysts, oxidising agents, reducing agents etc. may be used. Similarly, the reaction temperature and duration of the reaction may be adjusted according to the need.
An illustrative list of particular compounds according to the invention and capable of being produced by Schemes IA, IB to IX include:
Preferred group of compounds belonging to the compounds of Formulae IA, IB, II and III of the present invention are exemplified in Table I to Table IV though the present invention is not limited to the compounds given there.
All compounds mentioned in the above list as well as the compounds mentioned in formulae IA, IB, II and III with a variety of substituents were prepared using the methods described earlier depending upon whether they are mixtures of xcex1-methylated isomers, mixtures of non xcex1-methylated isomers or pure RR isomers.
The examples mentioned below demonstrate the general synthetic procedure as well as the specific preparation for the preferred compound. The examples are given to illustrate the details of the invention and should not be constrained to limit the scope of the present invention.
Most of the compounds were characterized using NMR, IR and were purified by chromatography. Crude products were subjected to column chromatographic purification using silica gel (100-200 or 60-120 mesh) as stationary phase.